The genetic basis for regulating the concentration of enzymes and other proteins is well established for microbial systems. On the other hand, an understanding of the fundamental mechanisms for regulating the tissue concentration of an enzyme in higher organisms is still quite limited. This project is designed to study regulatory mechanisms in higher organisms using a system in which genetics can be used to manipulate the biochemistry of mammalian tissues both during development and in the differentiated state. The enzymes to be studied include Delta-aminolevulinate dehydratase, lactate dehydrogenase, and glycolytic enzymes in tissues of inbred mouse strains. Mutant genes, which affect the tissue activity of these enzymes, have been identified. Among the specific questions to be asked are the following: (1) Do these genes affect the primary structure or the tissue concentration of enzymes? (2) What is the biochemical mechanism by which these genes exert their effect? (3) Do enzymes in developing liver and hepatomas differ from enzymes in differentiated cells? (4) What is the nature of the genetic regulation during development of the liver? (5) Can other mutant genes be found which also affect these enzyme systems? It is anticipated that a system of mutations affecting both structural genes and genes that regulate the concentration of specific proteins will provide a valuable tool to aid in the understanding of regulatory mechanisms in animal cells.